ABSTRACT: Maintaining Robust T Cell Immunity for Broad Protection Against Influenza Influenza vaccines currently in use are designed, primarily to produce neutralizing antibody to coat proteins and must be reformulated and given each year. They are only partially effective, while live infection confers highly protective T cell mediated immunity which provides multiple additional protective mechanisms and also is crucial for generation of long-lasting neutralizing Ab. Our recent studies indicate that generation of protective CD4 T cell immunity requires strong presentation of viral antigen and infection-mediated signals lasting at least a week. This is because the effectors need to receive these signals during a clear-cut checkpoint to complete their transition to memory. Current vaccines rarely supply Ag or the relevant pathogen-recognition signals (PRS) at optimal levels for this long. Moreover, human responses often depend on already generated memory T cells, and it is not known whether memory CD4 T cells must go through a similar checkpoint to re-generate secondary (20) memory responses. Here we will compare the in vivo 20 response of memory CD4 T cells generated by inactivated whole influenza vaccine vs. live infection and determine whether the 20 CD4 effectors also need Ag and pathogen signals at a comparable ?effector checkpoint?, via similar mechanisms, to re-generate 20 CD4 memory and if such memory does indeed provide strong heterosubtypic protection against multiple influenza A viruses. If so, it should be possible to augment vaccines to provide the Ag and pathogen signals both initially and at the checkpoint, and this should create a framework for a new generation of more effective vaccines against influenza that are more broadly protective and give long-lasting immunity. Moreover, it is likely that the same strategies could be applied to vaccines against other pathogens.